Microglial activation and neuro-inflammation regulate disease progression in diverse neurodegenerative di- seases (NDs), including but not limited to Alzheimer's Disease, Parkinson's Disease, and Tauopathies. Under- standing pathways that regulate neuro-inflammation in NDs is a significant goal. Cellular Prion Protein (PrPC) is best known as a GPI-anchored membrane protein that, in rare circumstances, undergoes conformational change to generate a derivative that aggregates in the brain, causing rapid ND and death. Pathogenic PrPC is trans- missible. Non-pathogenic PrPC is expressed widely, inside and outside the CNS. Numerous studies in diverse mouse model systems have shown that PrPC attenuates inflammatory responses, including neuro-inflammation. We contributed to this field by identifying a system of receptors that mediates the anti-inflammatory activity of PrPC in macrophages when PrPC is released from cells by ADAM family proteases (S-PrP) or in exosomes and other extracellular vesicles (EVs). This receptor system includes LDL Receptor-related Protein-1 (LRP1) and the NMDA Receptor (NMDA-R). Binding of PrPC derivatives to the LRP1/NMDA-R receptor assembly in mac- rophages blocks pro-inflammatory responses initiated by diverse Pattern Recognition Receptors. We now have data showing that the PrPC-LRP1/NMDA-R interaction initiates anti-inflammatory cell-signaling in microglia. We also have shown that the anti-inflammatory activity of S-PrP may be harnessed in small synthetic peptides (14- mers, 4-mer) corresponding to a putative LRP1-binding motif in PrPC that includes Lys100 and Lys103. The major goal of this research project is to characterize the activity of PrPC and the LRP1/NMDA-R receptor system in neuro-inflammation in NDs. A second goal is to test whether PrPC derivatives may be administered therapeu- tically to amplify the activity of the microglial LRP1/NMDA-R system and thereby attenuate neuro-inflammation. Three specific aims are proposed. In Specific Aim 1, we will test the ability of anti-inflammatory PrPC derivatives to regulate microglial activation and secretion of pro-inflammatory mediators by microglia and astrocytes in res- ponse to proteins that accumulate and aggregate in the extracellular spaces of the CNS in various NDs, including amyloid-β (Aβ), microtubule-associated protein Tau, and α-synuclein. In Specific Aim 2, the effects of PrPC gene (Prnp) deletion on biomarkers of microglial activation and neuro-inflammation will be studied in three distinct mouse models of ND, including AppNL-F mice, P301S-Tau transgenic mice, and mice that receive intracerebral injections of α-synuclein pre-formed fibrils. In Specific Aim 3, we will replicate the studies proposed in Specific Aim 2, studying tga20 mice, which express 3-4× more PrPC in the CNS compared with wild-type mice. Next, we will exploit the known ability of LRP1 to serve as a Blood-Brain Barrier Trojan Horse-receptor that transports proteins into the CNS and test whethe...